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Filamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions by providing elastic support and/or through signaling. An elastic region at the C-terminus of filamin is called the mechanosensitive region and has been proposed to sense and counteract contractile damage. Here we use molecularly defined mutants and microscopy analysis of the Drosophila indirect flight muscles to investigate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region to interrogate the mechanosensitive region and detected three Z-disc phenotypes: dissociation of actin filaments, Z-disc rupture, and Z-disc enlargement. We tested a constitutively closed filamin mutant, which prevents the elastic changes in the mechanosensitive region and results in ruptured Z-discs, and a constitutively open mutant which has the opposite elastic effect on the mechanosensitive region and gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, stabilizes the Z-disc, and counteracts contractile damage at the Z-disc.

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Developing semiconductor devices requires a fast and reliable source of strain information with high spatial resolution and strain sensitivity. This work investigates the strain in an axially heterostructured 180 nm-diameter GaInP nanowire with InP segments of varying lengths down to 9 nm, simultaneously probing both materials. Scanning X-ray diffraction (XRD) is compared with Bragg projection ptychography (BPP), a fast single-projection method. BPP offers a sufficient spatial resolution to reveal fine details within the largest segments, unlike scanning XRD. The spatial resolution affects the quantitative accuracy of the strain maps, where BPP shows much-improved agreement with an elastic 3D finite element model compared with scanning XRD. The sensitivity of BPP to small deviations from the Bragg condition is systematically investigated. The experimental confirmation of the model suggests that the large lattice mismatch of 1.52% is accommodated without defects.

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Pain is one of the most prevalent and difficult to manage symptoms in cancer patients, and conventional drugs present a range of adverse reactions. The development of ß-cyclodextrins (ß-CD) complexes has been used to avoid physicochemical and pharmacological limitations due to the lipophilicity of compounds such as p-Cymene (PC), a monoterpene with antinociceptive effects. Our aim was to obtain, characterize, and measure the effect of the complex of p-cymene and ß-cyclodextrin (PC/ß-CD) in a cancer pain model. Initially, molecular docking was performed to predict the viability of complex formation. Afterward, PC/ß-CD was obtained by slurry complexation, characterized by HPLC and NMR. Finally, PC/ß-CD was tested in a Sarcoma 180 (S180)-induced pain model. Molecular docking indicated that the occurrence of interaction between PC and ß-CD is favorable. PC/ß-CD showed complexation efficiency of 82.61%, and NMR demonstrated PC complexation in the ß-CD cavity. In the S180 cancer pain model, PC/ß-CD significantly reduced the mechanical hyperalgesia, spontaneous nociception, and nociception induced by non-noxious palpation at the doses tested (p < 0.05) when compared to vehicle differently from free PC (p > 0.05). Therefore, the complexation of PC in ß-CD was shown to improve the pharmacological effect of the drug as well as reducing the required dose.

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BACKGROUND: Breast cancer is rare in men. This population-based study aimed to determine outcomes of male breast cancer in relation to residence and other variables. METHODS: In this retrospective cohort study, men diagnosed with breast cancer in Saskatchewan during 2000-2019 were evaluated. Cox proportional multivariable regression analyses were performed to determine the correlation between survival and clinicopathological and contextual factors. RESULTS: One hundred-eight eligible patients with a median age of 69 years were identified. Of them, 16% had WHO performance status ≥ 2 and 61% were rural residents. The stage at diagnosis was as follows: stage 0, 7%; I, 31%; II, 42%; III, 11%; IV, 8%. Ninety-eight percent had hormone receptor-positive breast cancer. The median disease-free survival of urban patients was 97 (95% CI: 50-143) vs. 64 (46-82) months of rural patients (p = 0.29). The median OS of urban patients was 127 (94-159) vs. 93 (32-153) months for rural patients (p = 0.27). On multivariable analysis, performance status ≥ 2, hazard ratio (HR) 2.82 (1.14-6.94), lack of adjuvant systemic therapy, HR 2.47 (1.03-5.92), and node-positive disease, HR 2.32 (1.22-4.40) were significantly correlated with inferior disease-free survival in early-stage invasive breast cancer. Whereas stage IV disease, HR 7.8 (3.1-19.5), performance status ≥ 2, HR 3.25 (1.57-6.71), and age ≥ 65 years, HR 2.37 (1.13-5.0) were correlated with inferior overall survival in all stages. CONCLUSIONS: Although residence was not significantly correlated with outcomes, rural men had numerically inferior survival. Poor performance status, node-positive disease, and lack of adjuvant systemic therapy were correlated with inferior disease-free survival.

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One of the most intriguing features of multicellular animals is their ability to move. On a cellular level, this is accomplished by the rearrangement and reorganization of the cytoskeleton, a dynamic network of filamentous proteins which provides stability and structure in a stationary context, but also facilitates directed movement by contracting. The ALP/Enigma family proteins are a diverse group of docking proteins found in numerous cellular milieus and facilitate these processes among others. In vertebrates, they are characterized by having a PDZ domain in combination with one or three LIM domains. The family is comprised of CLP-36 (PDLIM1), Mystique (PDLIM2), ALP (PDLIM3), RIL (PDLIM4), ENH (PDLIM5), ZASP (PDLIM6), and Enigma (PDLIM7). In this review, we will outline the evolution and function of their protein domains which confers their versatility. Additionally, we highlight their role in different cellular environments, focusing specifically on recent advances in muscle research using Drosophila as a model organism. Finally, we show the relevance of this protein family to human myopathies and the development of muscle-related diseases.

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Farnesol (FAR) is a sesquiterpene alcohol with a range of reported biological effects including cardioprotective, antioxidant and antiarrhythmic properties. However, due to its volatility, the use of drug incorporation systems, such as cyclodextrins, have been proposed to improve its pharmacological properties. Thus, the aim of this study was to evaluate and characterize the cardiovascular effects of FAR alone, and to investigate the antihypertensive effects of FAR complexed with ß-cyclodextrin (ßCD) in rats. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after intravenous administration of FAR (0,5; 2,5; 5 and 7,5 mg/kg) in normotensive rats, and after oral acute administration (200 mg/kg) of FAR and FAR/ßCD complex in NG-nitro-L-arginine-methyl-ester (L-NAME) hypertensive rats. In normotensive animals, FAR induced dose-dependent hypotension associated with bradycardia. These effects were not affected by pre-treatment with L-NAME or indomethacin (INDO), but were partially attenuated by atropine. Pre-treatment with hexamethonium (HEXA) only affected hypotension. In the hypertensive rats, FAR/ßCD potentialized the antihypertensive effect when compared to FAR alone. Molecular docking experiments demonstrated for the first time that FAR has affinity to bind to the M3 and M2 muscarinic, and nicotinic receptors through hydrogen bonds in the same residues as known ligands. In conclusion, our results demonstrated that FAR induced hypotension associated with bradycardia, possibly through the muscarinic and nicotinic receptors. The inclusion complex with ßCD improved the antihypertensive effects of FAR, which can be relevant to improve current cardiovascular therapy using volatile natural components.

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The interest in metal halide perovskites has grown as impressive results have been shown in solar cells, light emitting devices, and scintillators, but this class of materials have a complex crystal structure that is only partially understood. In particular, the dynamics of the nanoscale ferroelastic domains in metal halide perovskites remains difficult to study. An ideal in situ imaging method for ferroelastic domains requires a challenging combination of high spatial resolution and long penetration depth. Here, we demonstrate in situ temperature-dependent imaging of ferroelastic domains in a single nanowire of metal halide perovskite, CsPbBr3. Scanning X-ray diffraction with a 60 nm beam was used to retrieve local structural properties for temperatures up to 140 °C. We observed a single Bragg peak at room temperature, but at 80 °C, four new Bragg peaks appeared, originating in different real-space domains. The domains were arranged in periodic stripes in the center and with a hatched pattern close to the edges. Reciprocal space mapping at 80 °C was used to quantify the local strain and lattice tilts, revealing the ferroelastic nature of the domains. The domains display a partial stability to further temperature changes. Our results show the dynamics of nanoscale ferroelastic domain formation within a single-crystal perovskite nanostructure, which is important both for the fundamental understanding of these materials and for the development of perovskite-based devices.

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Bovine papillomavirus (BPV) can cause damage to the epithelial and mucosal tissue and currently presents 28 known types. Not all BPV types are associated with the development of cancer in cattle. Studies have shown that variants of human papillomavirus types can present different pathogenic profiles. However, despite the similarity, it is not yet known whether variants of BPV types can also present varying degrees of pathogenicity. Thus, the aim of this study was to evaluate the genetic variability of BPV types and variants isolated in Northeastern Brazil. Samples were obtained from animals with papillomatous lesions. BPV DNA was detected by the amplification of the L1 gene and genotyping was performed by sequencing. Mutations were analyzed in a phylogenetic, structural and functional context. In total, 52 positive samples were obtained and 11 different BPV types were identified in the samples. Ten putative new BPV types were also identified. In addition, several non-synonymous mutations were identified and predicted to alter protein stability, having an impact on immune evasion. The study demonstrated a high genetic diversity of BPV in the region with a large number of mutations identified, serving as a basis for more efficient control measures to be adopted for bovine papillomatosis.

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Bragg coherent diffraction imaging is a powerful strain imaging tool, often limited by beam-induced sample instability for small particles and high power densities. Here, we devise and validate an adapted diffraction volume assembly algorithm, capable of recovering three-dimensional datasets from particles undergoing uncontrolled and unknown rotations. We apply the method to gold nanoparticles which rotate under the influence of a focused coherent x-ray beam, retrieving their three-dimensional shapes and strain fields. The results show that the sample instability problem can be overcome, enabling the use of fourth generation synchrotron sources for Bragg coherent diffraction imaging to their full potential.

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Talin is the major scaffold protein linking integrin receptors with the actin cytoskeleton. In Drosophila, extended Talin generates a stable link between the sarcomeric cytoskeleton and the tendon matrix at muscle attachment sites. Here, we identify phosphorylation sites on Drosophila Talin by mass spectrometry. Talin is phosphorylated in late embryogenesis when muscles differentiate, especially on T152 in the exposed loop of the F1 domain of the Talin head. Localization of a mutated version of Talin (Talin-T150/T152A) is reduced at muscle attachment sites and can only partially rescue muscle attachment compared with wild-type Talin. We also identify Slik as the kinase phosphorylating Talin at T152. Slik localizes to muscle attachment sites, and the absence of Slik reduces the localization of Talin at muscle attachment sites causing phenotypes similar to Talin-T150/T152A. Thus, our results demonstrate that Talin phosphorylation by Slik plays an important role in fine-tuning Talin recruitment to integrin adhesion sites and maintaining muscle attachment.

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BACKGROUND: Canine papillomavirus (CPV) has 20 described types associated with papillomas or squamous cell carcinoma (SCC). Knowledge about CPV diversity is scarce. Studies on papillomaviruses that infect other hosts show substantial diversity with some types and variants being associated with cancer. HYPOTHESIS/OBJECTIVES: The aim of this study was to assess the genetic variability of the capsid L1 gene of CPV identified in lesions of naturally infected dogs from Brazil. ANIMALS: Six dogs presenting with oral and cutaneous warts from different veterinary clinics in Sergipe state, Northeast Brazil. METHODS AND MATERIALS: Nine skin biopsy samples were collected for histopathological and molecular analyses. Bioinformatics tools were used for genotyping and diversity analysis. Mutations were characterized based on their impact on the L1 protein structure. RESULTS: Sequences of CPV1 were obtained from exophytic papillomas. These sequences had at least five different mutations showing that all sequences were putative CPV1 variants. One CPV1 sequence, obtained from an oral SCC, had a highly destabilizing substitution in the L1 protein which was likely to be associated with changes in protein function. CONCLUSIONS AND CLINICAL IMPORTANCE: Despite the small number of cases analysed and the partial analysis of L1 nucleotide and amino acid sequences, this study has demonstrated diversity in CPV samples from Northeast Brazil. A putative new CPV1 variant associated with oral SCC, with novel protein structure changing mutations, was identified which may be important for understanding papillomavirus pathogenesis.

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BACKGROUND: Bovine papillomavirus (BPV) belongs to the Papillomaviridae family and infects epithelial cells of bovines and closely related animals, causing hyperproliferative lesions known as warts or papillomas, which may regress or progress to form benign or malignant tumors. The virus enters the host cell and interacts with it by altering the regulation of genes that are responsible for controlling the cell cycle, thus triggering lesion formation. It is not yet known which host genes are regulated by viral infection. Therefore, the objective of this study was to make use of next-generation RNA sequencing methods to identify differentially expressed genes associated with BPV infection, which might elucidate possible marker genes that could be used to control the disease. RESULTS: Transcriptome analysis revealed that 1343 genes were differentially regulated (FDR < 0.05). A comparison of gene expression in infected and noninfected cows indicated that 655 genes were significantly upregulated, and 688 genes were significantly downregulated. Most differentially expressed genes were associated with BPV infection pathways, which supports the hypothesis that viral infection was the mechanism associated with this regulation. CONCLUSIONS: This is the first study that focused on a large-scale evaluation of gene expression associated with BPV infection, which is important to identify possible metabolic pathways regulated by host genes for lesion development. In addition, novel targets could be identified in order to find ligands that interact with BPV, with the aim of interrupting the infection cycle.

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Chagas disease represents one of the major health issue in Latin America. Epidemiological control is focused on disease vectors, so studies on the ecology of triatomine vectors constitute a central strategy. Recently, research at large spatial scale has been produced, and authors commonly rely on the assumption that geographical regions presenting good environmental conditions for most vector species are also those with high risk of infection. In the present work, we provide an explicit evaluation for this assumption. Employing species distribution models and epidemiological data for Chagas disease in Brazilian territory, our results show that species richness is a poor predictor for the observed pattern of Chagas disease occurrence. Species composition proved to be a better predictor. We stress that research on macroecology of infectious diseases should go beyond the analysis of biodiversity patterns and consider human infections as a central part of the focal ecological systems.

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INTRODUCTION: Robotic-assisted surgery (RAS) has emerged as an alternative minimally invasive surgical option. Despite its growing applicability, the frequent need for pneumoperitoneum and Trendelenburg position could significantly affect respiratory mechanics during RAS. AVATaR is an international multicenter observational study aiming to assess the incidence of postoperative pulmonary complications (PPC), to characterise current practices of mechanical ventilation (MV) and to evaluate a possible association between ventilatory parameters and PPC in patients undergoing RAS. METHODS AND ANALYSIS: AVATaR is an observational study of surgical patients undergoing MV for general anaesthesia for RAS. The primary outcome is the incidence of PPC during the first five postoperative days. Secondary outcomes include practice of MV, effect of surgical positioning on MV, effect of MV on clinical outcome and intraoperative complications. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of the Hospital Israelita Albert Einstein. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT02989415; Pre-results.

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In this work we attempt to directly observe anisotropic partial relaxation of epitaxial InAs islands using transmission electron microscopy (TEM) and synchrotron x-ray diffraction on a 15 nm thick InAs:GaAs nanomembrane. We show that under such conditions TEM provides improved real-space statistics, allowing the observation of partial relaxation processes that were not previously detected by other techniques or by usual TEM cross section images. Besides the fully coherent and fully relaxed islands that are known to exist above previously established critical thickness, we prove the existence of partially relaxed islands, where incomplete 60° half-loop misfit dislocations lead to a lattice relaxation along one of the 〈110〉 directions, keeping a strained lattice in the perpendicular direction. Although individual defects cannot be directly observed, their implications to the resulting island registry are identified and discussed within the frame of half-loops propagations.

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Parotoid glands of amphibians are known for the production of several biologically active compounds having pharmacological and toxic effects in mammals. In the present work, a protein fraction obtained from Rhinella schneideri parotoid gland (RsPP) was characterized to study its biological and toxic effects. Rhinella schneideri parotoid secretion is composed of up to 30% (w/w) of soluble proteins. Tandem mass spectrometric analysis of the RsPP identified 104 proteins, including actin, beta-actin, ribosomal proteins, catalase, galectin, and uncharacterized proteins; however, no peptidases were found, and this result was reinforced by the absence of proteolytic activity. In addition, RsPP did not exhibit pro-coagulant or antibacterial effects. However, pretreatment of mice with different doses of RsPP intraperitoneally inhibited carrageenan-induced paw edema and increased tissue myeloperoxidase activity. RsPP also reduced interleukin 1ß levels in the peritoneal cavities and cell migration in the peritoneal cavities of an animal model of carrageenan-induced peritonitis. Subchronic treatment of animals with RsPP for 7 consecutive days did not alter the serum biochemical, renal, or liver parameters. However, a significant reduction in blood leukocyte count was observed. Our results showed that R. schneideri parotoid secretion contains proteins with anti-inflammatory and slight toxic effects.

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OBJECTIVE: To evaluate infectious morbidity associated with long-term use of venous access devices. DESIGN: Prospective, observational study. SETTING: Comprehensive cancer center at a university hospital. PARTICIPANTS: 1431 consecutive patients with cancer requiring 1630 venous access devices for long-term use inserted between 1 June 1987 and 31 May 1989. MEASUREMENTS: Quantitative microbiologic tests to identify device-related bacteremia and fungemia, catheter tunnel infection, pocket infection in implantable port devices, and site infections; number of days the device remained in situ and time until infectious morbidity; vessel or device thrombosis and device breakage. RESULTS: At least one device-related infection occurred with 341 of 788 (43% [95% CI, 39% to 47%]) catheters compared with 57 of 680 (8% [CI, 6% to 10%]) completely implanted ports (P < or = 0.001). Device-related bacteremia or fungemia is the predominant infection occurring with catheters, whereas ports have a more equal distribution of pocket, site, and device-related bacteremia. The predominant organisms isolated in catheter-related bacteremia were gram-negative bacilli (55%) compared with gram-positive cocci (65.5%) in port-related bacteremia. The number of infections per 1000 device days was 2.77 (95% CI, 2.48 to 3.06) for catheters compared with 0.21 (CI, 0.16 to 0.27) for ports (P < or = 0.001). Based on a parametric model of time to first infection, devices lasted longer in patients with solid tumors than in those with hematopoietic tumors. Ports lasted longer than catheters across all patient groups. CONCLUSIONS: The incidence of infections per device-day was 12 times greater with catheters than with ports. Patients with solid tumors were the least likely to have device-related infectious morbidity compared with those with hematologic cancers. The reasons for the difference in infectious complications is uncertain but may be attributable to type of disease, intensity of therapy, frequency with which devices are accessed, or duration of neutropenia.

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OBJECTIVE: This study was performed to evaluate the effect of a silver-impregnated cuff on the incidence of catheter-related bacteremia/fungemia or tunnel tract infection in cancer patients with chronic dual-lumen tunneled venous access catheters. SUMMARY BACKGROUND DATA: Infection is a frequent and potentially life-threatening complication of tunneled chronic cuffed silastic central venous access catheters in cancer patients. Recent experience with antimicrobial silver-impregnated cuffs placed on nontunneled percutaneously inserted central venous catheters suggests that such a cuff may render the catheter less prone to infection. METHODS: The authors prospectively randomized 200 cancer patients to receive either a dual-lumen 10 French tunneled cuffed silastic central venous access catheter or the same catheter with a second more proximal subcutaneous silver-impregnated cuff. All patients then were followed prospectively for infectious morbidity until the device was removed or the patient died. RESULTS: The hazard rate for infection/day (95% confidence limits) was 0.0022 (0.0015 to 0.0030) for standard catheters compared with 0.0027 (0.0019 to 0.0037) for catheters with silver-impregnated cuffs (p = not significant). Regression analysis of infection-free interval of both catheter types shows no difference over the lifetime of catheter as well as the over the first 48 days after insertion. CONCLUSIONS: The study indicated no effect of a silver-impregnated cuff in decreasing the incidence of catheter-related bacteremias/fungemias, tunnel infections, or the spectrum of causative microorganisms involved in cancer patients with tunneled chronic venous access catheters.

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